Structure-guided design of pure orthosteric inhibitors of αIIbβ3 that prevent thrombosis but preserve hemostasis

Brian D. Adair, José L. Alonso, Johannes van Agthoven, Vincent Hayes, Hyun Sook Ahn, I-Shing Yu, Shu-Wha Lin, Jian-Ping Xiong, Mortimer Poncz and M. Amin Arnaout ()
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Brian D. Adair: Leukocyte Biology & Inflammation Program, and Structural Biology Program, Massachusetts General Hospital
José L. Alonso: Leukocyte Biology & Inflammation Program, and Structural Biology Program, Massachusetts General Hospital
Johannes van Agthoven: Leukocyte Biology & Inflammation Program, and Structural Biology Program, Massachusetts General Hospital
Vincent Hayes: Division of Hematology, The Childrens Hospital of Philadelphia
Hyun Sook Ahn: Division of Hematology, The Childrens Hospital of Philadelphia
I-Shing Yu: Laboratory Animal Center, College of Medicine, National Taiwan University
Shu-Wha Lin: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University
Jian-Ping Xiong: Leukocyte Biology & Inflammation Program, and Structural Biology Program, Massachusetts General Hospital
Mortimer Poncz: Division of Hematology, The Childrens Hospital of Philadelphia
M. Amin Arnaout: Leukocyte Biology & Inflammation Program, and Structural Biology Program, Massachusetts General Hospital

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract A prevailing dogma is that inhibition of vascular thrombosis by antagonizing platelet integrin αIIbβ3 cannot be achieved without compromising hemostasis, thus causing serious bleeding and increased morbidity and mortality. It is speculated that these adverse outcomes result from drug-induced activating conformational changes in αIIbβ3 but direct proof is lacking. Here, we report the structure-guided design of peptide Hr10 and a modified form of the partial agonist drug tirofiban that act as “pure” antagonists of αIIbβ3, i.e., they no longer induce the conformational changes in αIIbβ3. Both agents inhibit human platelet aggregation but preserve clot retraction. Hr10 and modified tirofiban are as effective as partial agonist drugs in inhibiting vascular thrombosis in humanized mice, but neither causes serious bleeding, establishing a causal link between partial agonism and impaired hemostasis. Pure orthosteric inhibitors of αIIbβ3 may thus provide safer alternatives for human therapy, and valuable tools to probe structure–activity relationships in integrins.

Date: 2020
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DOI: 10.1038/s41467-019-13928-2

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